The system of mitogen-activated protein kinase (MAPK) is known as a system involved in intracellular signal transduction.
MAPK system is a conserved eukaryotic signal transduction system, by which the receptor-mediated signals are converted to a variety of actions. MAPK system contains three types of protein kinases, namely, mitogen-activated protein kinase kinase kinase (MAPKKK), mitogen-activated protein kinase kinase (MAPKK), and mitogen-activated protein kinase (MAPK). MAPKK phosphorylates and activates MAPK, and MAPKKK phosphorylates and activates MAPKK (Nishida, E. et al., Trends Biochem. Sci. (1993) 18, 128; Blumer, K. J. et al., Trends Biochem. Sci. (1993) 19, 236; David R. J. et al., Trends Biochem. Sci. (1993) 19, 470; Marchall, C. J. et al., Cell (1995) 80, 179).
TGF-β-activated kinase 1 (TAK1), a member of the MAPKKK family, functions in the intracellular signal transduction system. The TAK1 protein was identified by Yamaguchi, K. et al. (Yamaguchi, K. et al., Science (1995) 270, 2008). The protein has been revealed to be involved in the signal transduction of TGF-β and to be activated by TGF-β.
TAK1 binding protein 1 (TAB1) binds to TAK1 and participates in the signal transduction system of TGF-β that activates TAK1. The TAB1 protein was identified by Shibuya, H. et al. (Shibuya, H. et al., Science (1996) 272, 1179-1182). TAB1 binds to TAK1 and activates the kinase activity of TAK1, thereby transducing the TGF-β signal.
A very recent report describes that TAK1 is also activated by tumor necrosis factor (TNF) and interleukin-1 (IL-1) (Shirakabe, K. et al., J. Biol. Chem. (1997) 272, 8141). It has also been reported that the activation of transcription factor NF-κB is induced after TAK1 activation (Moriguchi, T., et al., J. Biol. Chem. (1996) 271, 13675; Ponton, A., et al., J. Biol. Chem. (1996) 271, 8991; Sakurai S., et al., Biochem. Biophys. Res. Commun. (1998) 243, 545).
However, it is not at all known that the inhibition of signal transduction through TAK1 actually results in the inhibition of cellular responses to the inflammatory stimulation such as LPS or cytokine stimulation, for example, the inhibition of signal transduction through an inflammatory cytokine as an inflammatory mediator as well as results in the inhibition of inflammatory cytokine actions and further the inhibition of inflammatory cytokine production.